fosbretabulin and Neoplasm-Metastasis

Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins. In this review, we discuss the development of the combretastatins from nature to the clinic. The various mechanisms underlying combretastatin-induced cell cycle arrest, mitotic catastrophe, cell death, and survival are also reviewed in an attempt to further enhance the clinical prospects of this unique class of VTAs.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Hypoxia; Cell Movement; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Spindle Apparatus; Stilbenes; Tubulin Modulators

Anaplastic thyroid cancer (ATC) is a rare and deadly malignancy. There is a need to speed up and support clinical research. This review article focuses on the new molecules that have been developed for the treatment of this aggressive tumor.. Improvement in the knowledge of pathogenesis and genetics of ATC led to the development of a variety of new molecules that may be used to treat this disease. In summary, these molecules are proteasome inhibitors, Aurora kinase inhibitors, vascular targeting agents, and gene therapies. All these molecules demonstrated a potentially therapeutic activity in metastatic ATC. To date, the largest prospective randomized multicenter, open-label, trial was conducted with combretastatin-A4.. More efficient drugs need to be developed through multinational efforts.

Topics: Antineoplastic Agents, Phytogenic; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM).. Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression.. Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009).. There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bibenzyls; Carboplatin; Carcinoma; CD56 Antigen; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neural Cell Adhesion Molecules; Organophosphorus Compounds; Paclitaxel; Stilbenes; Survivors; Thyroid Neoplasms; Treatment Outcome; Young Adult

Although the polymeric vascular disrupting agent (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles (CA4-NPs) has great potential to inhibit cancer growth, it is still a challenge to avert tumor recurrence and metastasis after treatment. It is mainly tightly associated with hypoxia induced by CA4-NPs, which can activate many downstream genes regulating tumor growth and metastasis. Herein, to relieve a tumor hypoxia microenvironment, the mTOR inhibitor temsirolimus was employed to modulate the tumor microenvironment when treated with CA4-NPs. In vitro MTT experiments strongly verified that the combination of temsirolimus with polymeric CA4-NPs exhibited an additive toxicity to 4T1 cells. An in vivo study with the 4T1 mammary adenocarcinoma model revealed that consistent with the proposed scenario, combination therapy with CA4-NPs plus temsirolimus suppressed tumor growth significantly more strongly compared to either CA4-NPs or temsirolimus monotherapy, and the inhibition rate to 4T1 tumor with a volume of 300 mm

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Polyglutamic Acid; Polymers; Sirolimus; Stilbenes; Tumor Microenvironment

Hypoxia-activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors. After treatment with the combination of TPZ plus CA4-NPs, complete tumor reduction is observed in 4T1 xenograft mice (initial tumor volume is 180 mm

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Drug Synergism; Mice; Mice, Inbred BALB C; Nanomedicine; Neoplasm Metastasis; Prodrugs; Stilbenes; Tirapazamine; Tumor Hypoxia; Xenograft Model Antitumor Assays

Combretastatin A-4 (CA-4) is a natural cis-stilbene which interferes with the cellular tubulin dynamics and which selectively destroys tumour blood vessels. Its pharmacological shortcomings such as insufficient chemical stability, water solubility, and cytotoxicity can be remedied by employing its imidazole derivatives.. We studied 11 halogenated imidazole derivatives of CA-4 for their effects on the microtubule and actin cytoskeletons of cancer and endothelial cells and on the propensity of these cells to migrate across tissue barriers or to form blood vessel-like tubular structures.. A series of N-methyl-4-aryl-5-(4-ethoxyphenyl)-imidazoles proved far more efficacious than the lead CA-4 in growth inhibition assays against CA-4-resistant HT-29 colon carcinoma cells and generally more selective for cancer over nonmalignant cells. Et-brimamin (6), the most active compound, inhibited the growth of various cancer cell lines with IC50 (72 h) values in the low nanomolar range. Active imidazoles such as 6 reduced the motility and invasiveness of cancer cells by initiating the formation of actin stress fibres and focal adhesions as a response to the extensive microtubule disruption. The antimetastatic properties were ascertained in 3D-transwell migration assays which simulated the transgression of highly invasive melanoma cells through the extracellular matrix of solid tumours and through the endothelium of blood vessels. The studied imidazoles exhibited vascular-disrupting effects also against tumour xenografts that are refractory to CA-4. They were also less toxic and better tolerated by mice.. We deem the new imidazoles promising drug candidates for combination regimens with antiangiogenic VEGFR inhibitors.

Topics: Angiogenesis Inhibitors; Aniline Compounds; Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cell Movement; Chickens; Collagen; Cytoskeleton; Drug Combinations; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Laminin; Mice, Nude; Microtubules; Mitosis; Neoplasm Metastasis; Neovascularization, Physiologic; Proteoglycans; Stilbenes

We reported a precise engineered nanocapsule encapsulating a neovasculature disruption agent, combretastatin A4 (CA4) in a matrix that was made up of paclitaxel (PTX) conjugated amphiphilic polyester. The nanocapsule was able to release CA4 and PTX sequentially for temporal antiangiogenesis and anticancer activities. The nanocapsule has a small particle size at 68 nm with narrow size distribution (approximately 0.15). Cellular uptake of the nanocapsule was efficient, and detectable at as early as 20 min, and drugs sequestered in the nanocapsule could exert effective therapeutic effects on tumor neovasculature and cancer cells, respectively. Biodistribution experiments demonstrated the long circulation of nanocapsule in body fluid and the preferential accumulation of nanocapsule in tumor. Both in vivo artificial pro-angiogenesis and tumor xenograft assays demonstrated the promising therapeutic effect of the nanocapsule on tumor vasculature disruption, tumor cell proliferation inhibition and tumor cell apoptosis induction. The intrasplenic liver metastasis experiment also confirmed the liver metastatic prevention capacity of this nanocapsule. In summary, the findings indicated that this dual drug loaded nanocapsule with sequential drug delivery capacity is a promising candidate in combinatorial therapy in fighting against cancer, and may open an avenue for cancer therapy and diagnosis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Endocytosis; Endothelial Cells; Humans; Immunohistochemistry; Liver Neoplasms; Male; Mice; Nanocapsules; Neoplasm Metastasis; Neovascularization, Pathologic; Paclitaxel; Stilbenes

Combretastatin A4 (CA4) is a drug that targets tumor vasculature to inhibit angiogenesis. Whether CA4 has a direct effect on gastric cancer is not known. We herein investigated the effect of CA4 on growth and metastasis of gastric cancer cells at clinically achievable concentration and explored the associated antitumor mechanisms. Nine human gastric cancer cell lines, including two metastatic gastric cancer cell lines (AGS-GFPM1/2), constitutively expressing green fluorescence protein (GFP) were used. These metastatic AGS-GFPM1/2 cells expressed a higher level of phosphorylated serine 473 on AKT (p-AKT). Our results showed that CA4 (0.02-20 microM) has significant in vitro effects on reducing cell attachment, migration, invasiveness, as well as cell cycle G2/M disturbance on p-AKT-positive gastric cancer cells. In addition, a phosphoinositide 3-kinase inhibitor, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], a specific AKT inhibitor, and 0.2 to 20 microM CA4 displayed a similar response profile on p-AKT-positive cells, suggesting that CA4-induced effect was mediated by inhibition of the PI3 kinase/AKT pathway. The results from in vivo GFP monitoring system indicated that CA4 phosphate (CA4-P; 200 mg/kg) significantly inhibited the s.c. and intra-abdominal growth of xenotransplanted AGS-GFPM2 cells in nude mice. Furthermore, CA4-P treatment showed a remarkable ability to inhibit gastric tumor metastasis as well as attenuate p-AKT expression. In conclusion, our study is the first to find that CA4 inhibited AKT activity in human gastric cancer cells. The decreased AKT activity correlated well with the CA4 antitumor growth response and decrease of metastasis. Further investigation on drugs targeting the PI3 kinase-AKT pathway may provide a new approach for the treatment of human gastric cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Survival; Humans; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Stilbenes; Stomach Neoplasms; Xenograft Model Antitumor Assays